Leber’s hereditary optic neuropathy misdiagnosed as optic neuritis and Lyme disease in a patient with multiple sclerosis

Abstract

A 28-year-old Caucasian man developed sudden painless vision loss in the right eye. He was diagnosed with optic neuritis. MRI showed white matter lesions consistent with multiple sclerosis (MS), but no optic nerve enhancement. Eight months later, the left eye was affected in the same manner. Examination showed right optic atrophy and apparent left optic disc swelling. Workup revealed positive Lyme IgG. Differential diagnosis included optic neuritis and Lyme optic neuropathy, and he was treated with intravenous steroids, intravenous immunoglobulin, plasmapheresis and intravenous ceftriaxone without improvement. Neuro-ophthalmology consultation led to identification of pseudo-optic disc oedema, and Leber’s hereditary optic neuropathy (LHON) was suspected and confirmed by genetic testing. LHON may occur in association with MS, and should be considered in patients with MS with vision loss atypical for optic neuritis. This is especially important as new treatments for LHON (including gene therapy) are currently undergoing clinical trials.

Background

Vision loss in patients with multiple sclerosis (MS) is most commonly attributed to optic neuritis, which is caused by demyelination of the optic nerve. Optic neuritis typically presents with acute to subacute unilateral vision loss, and pain with eye movements occurs in over 90% of patients.¹ MRI findings associated with optic neuritis include T2 hyperintensity and T1 postcontrast enhancement of the optic nerve.² Visual acuity recovers to 20/40 or better in 92% of patients.³ Although none of these symptoms or signs of optic neuritis is 100% sensitive,^1–3 their absence should suggest consideration of alternative causes of vision loss.

This report describes a patient with MS who presented with vision loss without pain or MRI findings of optic neuritis and poor visual recovery. He was initially diagnosed and treated for optic neuritis then Lyme disease, before ultimately undergoing genetic testing confirming the diagnosis of Leber’s hereditary optic neuropathy (LHON).

Case presentation

A 28-year-old previously healthy Caucasian man presented with sudden painless vision loss of the right eye. He denied any systemic neurological symptoms. He was seen by an outside ophthalmologist and diagnosed with optic neuritis. Brain MRI was recommended, but he was lost to follow-up. Five months later, he sought ophthalmological care due to persistent vision loss. Visual acuity was hand motions in the right eye and 20/20 in the left eye. Ophthalmological examination was remarkable only for right afferent pupillary defect and optic atrophy. He underwent a brain MRI that demonstrated multiple enhancing and non-enhancing T2/FLAIR (Fluid-attenuated inversion recovery) hyperintensities of the white matter, with normal optic nerves (figure 1). He was treated with a course of intravenous steroids, without improvement in vision.

Figure 1.

MRI shows (A) absence of optic nerve enhancement on fat-suppressed postcontrast T1 axial scan of the orbit; (B) T2-hyperintense subcortical and periventricular white matter lesions on FLAIR sequence and (C) enhancement of the right frontal lesion and absence of enhancement of other lesions on the corresponding T1-weighted postcontrast scan, demonstrating that lesions are disseminated in both time and space.

Approximately 8 months after vision loss in the right eye, he developed painless vision loss of the left eye to counting fingers. The left optic nerve demonstrated mild swelling of the peripapillary retinal nerve fibre layer. The right optic nerve remained atrophic with visual acuity of hand motions. Fluorescein angiography demonstrated telangiectasias but no leakage of the left optic disc, consistent with pseudo-optic disc oedema (figure 2).

Figure 2.

Fundus photos of the (A) right and (B) left eyes demonstrate right optic atrophy and mild peripapillary retinal nerve fibre swelling in the left eye. (C) Late-phase fluorescein angiography of the left eye shows telangiectasias but no leakage of the optic disc, which confirms pseudo-optic disc oedema.

Investigations

MRI brain and orbits: Numerous white matter T2/FLAIR hyperintensities demonstrating dissemination in space and time. No optic nerve enhancement.

MRI cervical spine: Several foci of short-segment abnormal signal throughout the cervical cord, consistent with demyelination.

Aquaporin-4 (AQP-4) antibody: negative.

Myelin oligodendrocyte glycoprotein (MOG) antibody: negative.

Inflammatory and infectious labs including erythrocyte sedimentation rate (ESR), C reactive protein, anti-nuclear antibody (ANA), angiotensin converting enzyme (ACE), rapid plasma reagin (RPR), Lyme and Bartonella serology: within normal limits except for Lyme serology.

Lyme IgG (serum): 5/10 bands positive on western blot. Lyme DNA not detected by PCR.

Cerebrospinal fluid (CSF): normal protein, glucose and cell count; 12 oligoclonal bands. Negative Lyme IgG and IgM.

Targeted LHON mitochondrial DNA genetic testing: positive for m.11778G>A pathogenic mutation.

Differential diagnosis

Based on CSF oligoclonal bands and MRI findings consistent with MS, the patient was initially diagnosed with optic neuritis and MS. The diagnosis of MS was a radiological diagnosis, as he had no systemic neurological symptoms or signs. Although the orbital MRI did not demonstrate optic nerve enhancement, this did not exclude the diagnosis of typical demyelinating optic neuritis, which may occur in the absence of MRI findings.² Neuromyelitis optica (NMO) was also considered based on bilateral optic neuropathy with poor visual recovery, but AQP-4 and MOG antibodies were negative and brain and spine MRI were not consistent with NMO. Because Lyme IgG was positive on 5 of 10 western blot bands, the possibility of Lyme optic neuropathy was entertained. However, the clinical picture of painless, bilateral, sequential vision loss with poor visual recovery and pseudo-optic disc oedema in a young man was most consistent with LHON.

Treatment

The patient was started on glatiramer acetate for MS and received multiple courses of intravenous steroids without improvement in vision. He was referred to an infectious disease specialist, who diagnosed Lyme optic neuropathy and prescribed a course of intravenous ceftriaxone, which did not significantly affect his vision. Subsequently, his neurologist treated him with plasmapheresis and intravenous immunoglobulin for presumed refractory optic neuritis, and vision remained poor. Finally, neuro-ophthalmology consultation led to genetic testing confirming LHON and initiation of idebenone.

Outcome and follow-up

The visual acuity and visual field remain stable in the right eye; left eye visual acuity improved to 20/150 with a smaller central visual field defect at 9 months after onset of vision loss in the left eye.

Discussion

LHON is a mitochondrially inherited genetic disorder, with an estimated prevalence of 3.7 per 100 000 in a Northern European population.⁴ Three mitochondrial mutations (14484, 3460 and 11778) are responsible for over 90% of LHON cases.⁵ Classically, LHON presents with acute to subacute, bilateral, sequential and painless vision loss with generally poor visual recovery in young men, due to increased penetrance in men.⁶ LHON is frequently misdiagnosed initially as optic neuritis, due to acuity of onset, age at presentation and pseudo-optic disc oedema.⁶ Although the optic nerve is apparently swollen, fluorescein angiography shows circumpapillary telangiectasis without dye leakage from the optic disc, in contrast to optic neuritis with disc oedema (papillitis). In papillitis, inflammation at the optic nerve head leads to vascular leakage of dye, seen as hyperfluorescence of the optic disc that increases in area over time.⁷

This patient was diagnosed and treated for Lyme disease, which may be associated with brain MRI abnormalities similar to MS and is a rare cause of optic neuropathy.⁸ Establishing Lyme neuroborreliosis as the cause of optic neuropathy is complicated by the high rate of asymptomatic Lyme exposure in endemic regions.⁹ Strong evidence for Lyme optic neuropathy requires serological or culture positivity (preferably in the CSF), presence of other symptoms classically associated with Lyme disease (erythema migrans, facial nerve palsy or encephalitis/meningitis) and risk of tick bites.^{8 9} Our patient had negative CSF Lyme IgG, IgM and PCR, and no other symptoms of Lyme disease.

In addition to LHON, this patient was diagnosed with MS based on CSF oligoclonal bands and characteristic findings on the brain and cervical spine MRI. An association between LHON and MS has been previously described and termed Harding’s disease.¹⁰ More recently, Pfeffer et al analysed UK national survey results to identify patients with both LHON and MS, and determined that the number (12) was not higher than would be expected by chance.¹¹ However, the characteristics of optic neuropathy in patients with both LHON and MS were different from either disorder alone. Patients with LHON-MS were more commonly female and had longer duration between vision loss in the first and second eye than most patients with LHON; however, they also had absence of eye pain and poor visual recovery, which is atypical for MS-associated optic neuritis. Thus, although LHON may not increase risk of MS, the combination of diagnoses may affect the clinical presentation. A mechanistic interaction is possible, given that certain mitochondrial haplogroups have been associated with MS risk and mitochondrial respiratory chain activity is decreased in some MS lesions.¹²

The currently accepted therapy for LHON is idebenone, which has been demonstrated to improve visual acuity in a subset of patients.¹³ Spontaneous visual recovery occurs in some patients, most commonly those with the 14484 mutation.⁶ Gene therapy is an exciting new treatment possibility, but the results are preliminary and research is ongoing.¹⁴ This patient was ineligible for gene therapy trials due to comorbid MS.

Learning points.

• Vision loss in patients with multiple sclerosis (MS) with features atypical for optic neuritis (such as poor visual recovery, absence of eye pain and no optic nerve enhancement/T2 hyperintensity on MRI) should raise suspicion for an alternate diagnosis.

• Leber’s hereditary optic neuropathy (LHON) should be considered in patients with acute to subacute, painless, bilateral, sequential vision loss with poor visual recovery, even in the presence of another neurological diagnosis. Fluorescein angiography may help differentiate between optic neuritis and LHON.

• High rates of positive Lyme IgG occur in endemic areas, and diagnosis of Lyme optic neuropathy requires other symptoms classically associated with Lyme disease and risk of tick bites, in addition to positive serology and/or culture (preferably from the cerebrospinal fluid).

• LHON may occur in association with MS, and clinical presentation of optic neuropathy in patients with both diagnoses may differ from either condition alone.

• Gene therapy is a promising new avenue of treatment for LHON, and clinical trials are ongoing.